VAC14 oligomerization is essential for the function of the FAB1/PIKfyve-VAC14-FIG4 complex.

ABSTRACT: The PIKfyve-VAC14-FIG4 complex synthesizes and turns over phosphatidylinositol-3,5-bisphosphate, PI(3,5)P₂, an essential signaling lipid. A medium-resolution structure revealed that VAC14 forms a star-shaped pentamer scaffold. Two legs of VAC14 bind FIG4, with one leg also occupied by PIKfyve. The significance of VAC14 oligomerization was unknown. Here, using Alphafold2 and cryogenic electron microscopy maps we generated an atomic-resolution prediction, and found that some mutations linked to pediatric neurodegenerative diseases reside in the VAC14-VAC14 interfaces. A corresponding yeast mutation, along with additional mutations, demonstrates that VAC14 oligomerization is critical for Fab1/PIKfyve function. These mutations cause defects in the generation of PI(3,5)P₂,

SUBMITTER: Zhang L 

PROVIDER: S-EPMC12260172 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature